Cecconi F, Micheletti C, Carloni P, Maritan A
International School for Advanced Studies, Trieste, Italy.
Proteins. 2001 Jun 1;43(4):365-72.
Drug resistance to HIV-1 protease involves the accumulation of multiple mutations in the protein. We investigate the role of these mutations by using molecular dynamics simulations that exploit the influence of the native-state topology in the folding process. Our calculations show that sites contributing to phenotypic resistance of FDA-approved drugs are among the most sensitive positions for the stability of partially folded states and should play a relevant role in the folding process. Furthermore, associations between amino acid sites mutating under drug treatment are shown to be statistically correlated. The striking correlation between clinical data and our calculations suggest a novel approach to the design of drugs tailored to bind regions crucial not only for protein function, but for folding as well.
对HIV-1蛋白酶的耐药性涉及该蛋白中多个突变的积累。我们通过利用分子动力学模拟来研究这些突变的作用，该模拟利用了天然状态拓扑结构在折叠过程中的影响。我们的计算表明，对FDA批准药物的表型耐药性有贡献的位点是部分折叠状态稳定性最敏感的位置之一，并且应该在折叠过程中发挥相关作用。此外，药物治疗下发生突变的氨基酸位点之间的关联显示出统计学相关性。临床数据与我们的计算之间惊人的相关性表明了一种新的药物设计方法，该方法专门针对不仅对蛋白质功能至关重要，而且对折叠也至关重要的结合区域。
